Antimicrobial compounds and nanostructures

ABSTRACT

The present disclosure provides compounds and nanostructures having one or more quaternary ammonium salts, compositions including the compounds and nanostructures, and methods useful for treating conditions using the compounds, nanostructures, and compositions. In at least one aspect, a compound is represented by formula (I): 
                         
or a pharmaceutically acceptable salt thereof, wherein:
     Q is fluoro, chloro, bromo, or iodo;   each of s, b, and n is independently an integer from about 10 to about 100; and   each of v, j, p, z, q, x and m is independently an integer from 1 to about 20.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is continuation application of U.S. non-provisionalpatent application Ser. No. 15/838,751, filed Dec. 12, 2017, whichclaims priority to and the benefit of U.S. provisional patentapplication Ser. No. 62/521,040 filed Jun. 16, 2017. Each of theaforementioned patent applications is incorporated herein by referencein its entirety.

FIELD

The present disclosure provides compounds and nanostructures having oneor more quaternary ammonium salts, compositions including the compoundsand nanostructures, and methods useful for treating conditions using thecompounds, nanostructures, and compositions.

BACKGROUND

Preventing disease transmission on aircraft has conventionally focusedon improvements of the air-conditioning/filtration systems. Recentresearch has suggested that one way to further improve diseaseprevention on aircraft and spacecraft can include surface contaminationtreatment, e.g. on surfaces of the aircraft. However, while someantimicrobial compounds have been produced for antibacterialapplications, no compound has been demonstrated specifically forantiviral applications. For antiviral compounds, the biotechnology andpharmaceutical industries use proteins and small molecules (e.g.,molecular weight less than 1,000) to target microbes. However, proteinsand small molecules have limited systemic half-lives and, in turn,typically involve higher dosages than is desired.

Furthermore, hydrophobic binding of existing antimicrobial materialsrequires long dehydration times before being effective such that aconsiderable amount of microbe transmission occurs during thedehydration, such that antimicrobial activity is not efficacious againststrong microbes (such as Escherichia coli (E. coli)).

Therefore, there is a need for antimicrobial compounds andnanostructures capable of further functionalization and antimicrobialactivity against strong microbes (such as E. coli), compositionsincluding the compounds and nanostructures, and methods useful forantimicrobial and/or antiviral applications using the compounds,nanostructures, and compositions.

SUMMARY

The present disclosure provides compounds and nanostructures having oneor more quaternary ammonium salts, compositions including the compoundsand nanostructures, and methods useful for treating conditions (such asviruses and toxin-related conditions) using the compounds,nanostructures, and compositions.

At least one compound is represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein:Q is fluoro, chloro, bromo, or iodo;each of s, b, and n is independently an integer from about 10 to about100; andeach of v, j, p, z, q, x and m is independently an integer from 1 toabout 20.

At least one composition of the present disclosure includes a compoundrepresented by formula (I), or a pharmaceutically acceptable saltthereof, and one or more additional components. The composition can havea three dimensional conformation that is a nanoworm or nanorod.

At least one method includes depositing a compound or composition of thepresent disclosure onto an object, such as an internal surface of anaircraft. At least one method includes a method for treating a conditioncomprising administering to a subject a therapeutically effective amountof a compound represented by formula (I), or a pharmaceuticallyacceptable salt thereof, (or a composition including a compoundrepresented by formula (I), or a pharmaceutically acceptable saltthereof), wherein the condition to be treated includes viral infections,bacterial infections, chronic inflammatory disorders, acute inflammatorydisorders, or cancer.

At least one method includes preparing a compound of formula (I), orpharmaceutically acceptable salt thereof. At least one method includespreparing a composition including a compound of formula (I), orpharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

So that the manner in which the above recited features of the presentdisclosure can be understood in detail, a more particular description ofthe disclosure, briefly summarized above, may be had by reference toaspects, some of which are illustrated in the appended drawings. It isto be noted, however, that the appended drawings illustrate only typicalaspects of this present disclosure and are therefore not to beconsidered limiting of its scope, for the present disclosure may admitto other equally effective aspects.

FIG. 1 is a ¹H nuclear magnetic spectrum of the polymer in deuteratedchloroform, according to one aspect.

FIG. 2A is a ¹H NMR spectrum of maleimide functionalquaternized-poly-DMAEA in deuterated water, according to one aspect.

FIG. 2B is a ¹H NMR spectrum of maleimide functionalquaternized-poly-DMAEA in deuterated water, according to one aspect.

FIG. 2C is a ¹H NMR spectrum of maleimide functionalquaternized-poly-DMAEA in deuterated water, according to one aspect.

FIG. 3 is a scheme illustrating conjugation of maleimide functionalcationic polymer to Dopa- and PDS-functional nanoworms, according to oneaspect.

FIG. 4 is a bar graph illustrating the inhibitory effects of severalpolymers of the present disclosure against E. coli cultures, accordingto one aspect.

FIG. 5A is scanning electron microscope images showing a blank and E.coli control, according to one aspect.

FIG. 5B is scanning electron microscope images showing antibacterialactivity of several cationic polymer nanoworms of the present disclosureagainst E. coli, according to one aspect.

FIG. 5C is scanning electron microscope images showing antibacterialactivity of several cationic polymer nanoworms of the present disclosureagainst E. coli, according to one aspect.

FIG. 5D is scanning electron microscope images showing antibacterialactivity of several cationic polymer nanoworms of the present disclosureagainst E. coli, according to one aspect.

To facilitate understanding, identical reference numerals have beenused, where possible, to designate identical elements that are common tothe figures. The figures are not drawn to scale and may be simplifiedfor clarity. It is contemplated that elements and features of one aspectmay be beneficially incorporated in other aspects without furtherrecitation.

DETAILED DESCRIPTION

The present disclosure provides compounds and nanostructures having oneor more quaternary ammonium salts, compositions including the compoundsand nanostructures, and methods useful for treating conditions using thecompounds, nanostructures, and compositions.

Compounds

In at least one aspect, a compound is represented by formula (I):

or a pharmaceutically acceptable salt thereof, where Q is fluoro,chloro, bromo, or iodo, preferably chloro;each of s, b, and n is independently an integer from about 10 to about100; andeach of v, j, p, z, q, x and m is independently an integer from 1 toabout 20.

In at least one aspect, s is an integer from about 20 to about 40, suchas about 25 to about 35. b can be an integer from about 30 to about 60,such as from about 40 to about 50. n can be an integer from about 30 toabout 60, such as from about 50 to about 60. m can be an integer fromabout 1 to about 10, such as from about 5 to about 10. x can be aninteger from about 5 to about 15, for example 7, 11, or 15.

Without being bound by theory, x values from about 5 to about 15 providecell membrane penetration of the alkyl moiety into the hydrophobicportion of a cell membrane (such as a viral cell), while the cationicnitrogen moieties of the compound of formula (I) provide coulombicinteractions of the compound of formula (I) (such as the quaternaryammonium moieties) with the cell membrane surface (such as the phosphatemoieties of the phospholipid bilayer). Furthermore, the quaternaryammonium salt provides sufficient hydrophilicity so that the alkylmoieties attached to the quaternary ammonium salt do not becomesubstantially buried within the core of the three dimensional structure(e.g., when the composition has the three dimensional structure ofnanoworm or nanorod).

The polystyrene block of the compound of formula (I) can provide a highglass transition temperature (Tg) component to the compound of formula(I) (100% polystyrene has a Tg of about 100° C.). The high Tg providesstability to the nanostructures at body temperature. Furthermore, thepoly(N-isopropylacrylamide) (poly-NIPAM) block can provide a nanoworm(or nanorod) three dimensional conformation of the compound of formula(I) under aqueous conditions, e.g. an aqueous solution containing sodiumdodecyl sulfate (SDS).

The ratio of the integer n to the integer m can be selected to fine tunethe coulombic binding ability versus cell membrane penetratingcapability of a compound of formula (I). A higher integer n valueprovides increased coulombic binding, while a higher integer m providesincreased cell membrane penetrating capability of a compound of formula(I). In at least one aspect, a ratio of the integer n to the integer mis from about 1:1 to about 100:1, such as from about 5:1 to about 15:1,for example 54:7.

The values of v, j, p, z, and q can be varied based on the number of,for example, methylene units of the starting materials used to form thecompounds of formula (I). The value of s can be controlled bycontrolling the molar ratio of styrene monomers to NIPAM monomers andmaleimide starting materials, as described in more detail below.Similarly, the value of b can be controlled by controlling the molarratio of NIPAM monomers to styrene monomers and maleimide startingmaterials. The values of n and m can be controlled by the ratio of, forexample, methyl halide to other alkyl halide (e.g., octyl halide) usedto form the quaternary ammonium salt moieties.

In at least one aspect, the compound represented by formula (I) isrepresented by formula (II):

or a pharmaceutically acceptable salt thereof, where Q is fluoro,chloro, bromo, or iodo, preferably chloro;each of s, b, and n is independently an integer from about 10 to about100; andeach of x and m is independently an integer from 1 to about 20.

In at least one aspect, s of formula (II) is an integer from about 20 toabout 40, such as from about 25 to about 35. b of formula (II) can be aninteger from about 30 to about 60, such as from about 40 to about 50. nof formula (II) can be an integer from about 30 to about 60, such asfrom about 50 to about 60. m of formula (II) can be an integer fromabout 1 to about 10, such as from about 5 to about 10. x of formula (II)can be an integer from about 5 to about 15.

In at least one aspect, the compound represented by formula (I) orformula (II) is represented by formula (III):

or a pharmaceutically acceptable salt thereof, where x is an integerfrom about 5 to about 15, for example 7, 11, or 15.Compositions:

A compound represented by formula (I), formula (II), or formula (III),or a pharmaceutically acceptable salt thereof, can be present in acomposition with one or more additional components. Additionalcomponents can include one or more pharmaceutically active compounds.

In at least one aspect, a composition includes a compound represented byformula (I):

(I), or a pharmaceutically acceptable salt thereof, where Q is fluoro,chloro, bromo, or iodo, preferably chloro;each of s, b, and n is independently an integer from about 10 to about100; andeach of v, j, p, z, q, x and m is independently an integer from 1 toabout 20.

In at least one aspect, s is an integer from about 20 to about 40, suchas about 25 to about 35. b can be an integer from about 30 to about 60,such as from about 40 to about 50. n can be an integer from about 30 toabout 60, such as from about 50 to about 60. m can be an integer fromabout 1 to about 10, such as from about 5 to about 10. x can be aninteger from about 5 to about 15, for example 7, 11, or 15.

In at least one aspect, a ratio of the integer n to the integer m isfrom about 1:1 to about 100:1, such as from about 5:1 to about 15:1, forexample 54:7.

In at least one aspect, the compound represented by formula (I) isrepresented by formula (II):

or a pharmaceutically acceptable salt thereof, where Q is fluoro,chloro, bromo, or iodo, preferably chloro;each of s, b, and n is independently an integer from about 10 to about100; andeach of x and m is independently an integer from 1 to about 20.

In at least one aspect, s of formula (II) is an integer from about 20 toabout 40, such as from about 25 to about 35. b of formula (II) can be aninteger from about 30 to about 60, such as from about 40 to about 50. nof formula (II) can be an integer from about 30 to about 60, such asfrom about 50 to about 60. m of formula (II) can be an integer fromabout 1 to about 10, such as from about 5 to about 10. x of formula (II)can be an integer from about 5 to about 15.

In at least one aspect, the compound represented by formula (I) orformula (II) is represented by formula (III):

or a pharmaceutically acceptable salt thereof, where x is an integerfrom about 5 to about 15, for example 7, 11, or 15.

Compositions of the present disclosure can further include an additionalcomponent that is a compound represented by formula (IV):

or a pharmaceutically acceptable salt thereof, where each of s and b offormula (IV) is independently an integer from about 10 to about 100;v of formula (IV) is an integer from about 1 to about 20;R¹ is —O— or —NH—; and

R² is —CH₃, biotin, pyridyl disulfide, dopa, thiolactone, or adamantyl.Biotin can be of the structure:

Pyridyl disulfide can be of the structure:

Dopa can be of the structure:

Thiolactone can be γ-thiolactone of the structure

Adamantyl can be of the structure

R² as pyridyl disulfide is particularly advantageous because it can befurther conjugated to a pharmaceutically active moiety. Pharmaceuticallyactive moieties include polymers, sugars, peptides, oligonucleotides,proteins, or small molecule (e.g., 2,000 g/mol or less) therapeuticdrugs, such as an anticancer drug. Proteins include glycoproteins, suchas Vitornectin. Small molecule therapeutic drugs include Relenzabinders. Peptides include twin-arginine or translocation (TAT) peptide.Oligonucleotides include siRNA.

Furthermore, pyridyl disulfide can undergo thiol-disulfide exchange orthiol-ene reactions, Dopa can bind to a metal surface, γ-thiolactone canundergo an amination reaction (e.g., with an amino acid), biotin canbind to a biomolecule (e.g., streptavidin), and adamantly can bebrominated, fluorinated, carboxylated, or hydroxylated.

In at least one aspect, s of formula (IV) is an integer from about 25 toabout 35. b of formula (IV) can be an integer from about 40 to about 50.v of formula (IV) can be an integer from 1 to about 10, for example 2.

In at least one aspect, the compound represented by formula (IV) is oneor more of the compounds represented by formula (V), formula (VI), orformula (VII), or pharmaceutically acceptable salts thereof:

where s is an integer from about 25 to about 35 and b is an integer fromabout 40 to about 50.

In at least one aspect, a ratio of the compound represented by formula(I), (II), or (III) to the compound represented by formula (IV), formula(V), formula (VI), or formula (VII) is from about 0.01:1 to about1:0.01.

In at least one aspect, a composition includes a compound represented byformula (I), (II), or (III), a compound represented by formula (V), andan additional compound represented by formula (IV). A ratio of thecompound represented by formula (I), (II), or (III) to the compoundrepresented by formula (V) to the compound represented by formula (IV)is from about 0.99:0.005:0.005 to about 0.01:0.09:0.009, such as fromabout 0.9:0.05:0.05 to about 0.1:0.08:0.01, such as from about0.8:0.1:0.1 to about 0.1:0.1:0.8.

Three Dimensional Structures of a Compound or Composition

Long and flexible worms have in vivo blood circulation times about 10times longer than their spherical analogues and have significantlylonger circulation times than any synthetic particle or polyethyleneoxide-coated vesicles. Short rods, on the other hand, have much shortercirculation times but are more efficiently taken up by cells.

Compounds or compositions of the present disclosure can have a3-dimensional structure that is a nanoworm or nanorod. A nanorod canhave an aspect ratio from about 10:1 to about 1000:1, such as from about10:1 to about 100:1, such as from about 25:1 to about 75:1. A nanorodcan have a diameter from about 10 nm to about 20 nm and a length fromabout 100 nm to about 10 microns, such as from about 1 micron to about 2microns.

Compounds and compositions of the present disclosure can also have athree dimensional structure that is a sphere, vesicle, donut or lamellasheet. The three dimensional structure of compositions of the presentdisclosure can be stable in water for long periods of time (e.g., ananoworm stable for a year or more at room temperature) and can also befreeze-dried and rehydrated without structural reorganization. Forexample, a nanoworm solution can be freeze-dried to give dry power. Thefreeze-dried product can be rehydrated in Milli-Q water at ˜8 wt % for 2h. The ability of a composition of the present disclosure to befreeze-dried provides stable transportation of compositions of thepresent disclosure.

Nanoworm Formation

Preparation of functional thermo-responsive polymer nanorodsRAFT-mediated polymerization of styrene with functional poly(NIPAM)macro chain transfer agent (macroCTA) in water:

Precursor compounds (e.g., a compound represented by formula (I) butwithout the polystyrene block) can be mixed with styrene, sodium dodecylsulfate, and azobisisobutyronitrile (AIBN) in water (such as Milli-Qwater) to form a reaction mixture. One or more additional precursorcompounds (e.g., a compound represented by formula (IV) but without thepolystyrene block) can also be added to the reaction mixture.

AIBN can be dissolved in styrene followed by addition of the solutioninto a flask containing the other reaction components to form thereaction mixture. The solution of AIBN and styrene can be deoxygenatedby purging with Argon for, for example, about 15 minutes. The reactionmixture can be purged with Argon for, for example, about 10 minutes inan ice bath before heating to 70° C. for about 3.5 hours to form aproduct mixture.

The number average molecular weight (Mn) of the compounds of formula(IV) in the product mixture is determined by nuclear magnetic resonancespectroscopy, unless stated otherwise. ¹H NMR can be measured byfreeze-drying the product mixture to remove all water and low boilingpoint compounds and then dissolving the product mixture in CDCl₃. A sizeexclusion chromatography spectrum can be obtained by taking 3 drops oflatex and dissolving in 1 mL of THF, filtering and injecting thesolution into the SEC apparatus.

Alternatively, conversion of styrene monomers can be determined bygravimetry. The theoretic molecular weights can be calculated based onthe monomer conversions. The molecular weights (M_(n(SEC))) andPDI_(SEC) can be obtained by THF SEC. The molecular weights (M_(n(NMR)))is obtained from ¹H NMR. The particle size (D_(h)) and the particle sizedistribution (PDI_(DLS)) can be measured by dynamic light scattering(DLS) at 70° C. immediately after stopping the reaction, the resultswere the average value based on three measurements. PDI_(DLS)<0.1 meansnarrow distribution.

Nanoworms Cut into Nanorods Using Ultrasound.

Nanorods can be obtained by temperature directed morphologytransformation (TDTM) and ultrasound cutting of the nanoworms. In atleast one aspect, a 6 mL latex solution of a nanoworm can be transferredto 2 hot vials (3 mL each) with 60 SL of toluene in each vials. Thesevials can then be sealed and shaken. The suspensions in these vials canbe cooled to 23° C. The latex solutions can be cooled from 70° C. to 15°C. for about 30 min. The nanostructure can be characterized bytransmission electron microscopy (TEM) to confirm the formation ofworm-like nanostructures. To form the rods, the worms can be diluted byadding 10 mL of Milli-Q water, and cut using an ultrasound probe (withthe pulse of 3 s on and 2 s off as one pulse cycle) for 3 min in anice-bath at 35% amplitude (3 mm Tapered Micro Tip, VC-750 system fromSonics & Materials). After ultrasound cutting, the nanostructure can becharacterized by TEM again to confirm the formation of rods.

Ultrasonic cutting of nanoworms to nanorods can also be carried out byapplying probed ultrasound with different pulse cycles (15 seconds onand 10 seconds off as one pulse cycle), (B) 12 cycles (3 min), (C) 36cycles (9 min) and (D) 48 cycles (12 min).

In at least one aspect, heating a nanoworm or nanorod composition of thepresent disclosure above the lower critical solution temperature (LCST)(about 37° C.) of the PNIPAM block can produce a gel that when cooledcan dissociate back to a sol; a process that is reversible. Nanowormscan form gels at a minimum weight fraction of from about 1 wt % to about8 wt % in an aqueous solution. Nanorods can form gels at a minimumweight fraction of from about 2 wt % to about 16 wt % in an aqueoussolution. Without being bound by theory, gels are advantageous becausethey can be dissociated with increased temperature (such as from roomtemperature to body temperature of a subject, such as a human) to allowthe worm 3-dimensional structure to dissociate and move through theblood.

The weight percentages of the nanorods in water at which the gel can beformed at 37° C. can be measured as follows: generally, the freeze-driednanorods (e.g., 20 mg) can be redispersed in Milli-Q water by vortexingat 30 wt % in a 1.5 ml Eppendorf tube at 25° C. The tube can then becapped and immersed in a water bath at 37° C. for 2 min. The tube canthen be flipped under the water bath to observe the gel formation. Gelformation is defined as no observable flowing of the fluid within 30seconds. The weight percentage can be lowered by adding more Milli-Qwater and vortexing. The gel formation can then be checked again. Theminimum weight percentage of the nanorods, for example, in water to formthe gel at 37° C. is defined as wt % to form the gel.

Preferred Method of Synthesizing Compounds of Formula (I)

A preferred method of synthesizing compounds represented by formula (I)is shown in Scheme 1. A pyridyl disulfide capped diblock copolymer isreacted with a maleimide capped quaternary ammonium polymer in thepresence of tris(2-carboxyethyl)phosphine (TCEP) in water to form acompound represented by formula (I). The pyridyl disulfide cappeddiblock copolymer can be a compound represented by formula (IV) or (V)as a starting material to react with the maleimide capped quaternaryammonium polymer to form a compound represented by formula (I).

Methods for Depositing Compounds and Compositions

Compounds and compositions of the present disclosure may be depositedonto a surface of an object by any suitable deposition method.Deposition methods can include one or more of painting, dipping,spraying, marking, taping, brush coating, spin coating, roll coating,doctor-blade coating. Before deposition, a compound or composition ofthe present disclosure can be diluted in a solvent, such as water. Afterdeposition, the solvent may then evaporate at room temperature forming acompound/composition layer on the object.

In at least one aspect, the object is an interior surface of anaircraft/spacecraft/boat or an air filter surface of anaircraft/spacecraft/boat, such as a surface of an air-conditioning orfiltration system. The object can be a floor surface, seat surface,overhead bin surface, ceiling surface, door surface and/or door handlesurface of the interior of an aircraft.

In at least one aspect, a compound or composition of the presentdisclosure is sprayed onto a surface of an object for from about 1second to about 10 minutes, such as from about 30 seconds to about 2minutes. In at least one aspect, a compound or composition is sprayedonto a surface of an object in an amount from about 1 mL to about 25 kL,such as from about 100 L to about 1 kL.

Compounds or compositions of the present disclosure disposed on anobject prevents, reduces, and/or eliminates the presence of bacteria andviruses, which can prevent, reduce, and/or eliminate human contact withsuch bacteria and viruses.

Compositions comprising nanostructures (e.g., nanorods or nanoworms) ofthe present disclosure are advantageous to deposit onto a surfacebecause, for example, an antibacterial and antiviral compound can beapplied as a single layer, maintaining efficacy of both compounds. Asmentioned above, applying compositions having, for example, aconventional antimicrobial compound can be applied to a surface to forma first layer on the surface. A composition having, for example, aconventional antiviral compound can be applied to the first layer toform a second layer. However, the second layer (the antiviral layer)would mask the antimicrobial first layer (hindering its antimicrobialcapabilities).

Applying a composition having a nanostructure as a single layer alsoreduces cost and time of applying the compounds to a surface, ascompared to application of two or more layers.

Methods for Use as a Pharmaceutical Drug

The present disclosure further provides methods for treating a conditionin a subject having or susceptible to having such a condition, byadministering to the subject a therapeutically-effective amount of oneor more compounds or compositions as described above. In one aspect, thetreatment is preventative treatment. In another aspect, the treatment ispalliative treatment. In another aspect, the treatment is restorativetreatment.

A method for treating a condition can include administering to a subjecta therapeutically effective amount of a compound represented by formula(I), or pharmaceutically acceptable salt thereof (or a compositionhaving a compound represented by formula (I), or pharmaceuticallyacceptable salt thereof).

1. Conditions

The conditions that can be treated in accordance with the presentdisclosure include, but are not limited to, conditions caused by a toxin(such as an antigen) and inflammatory disorders such as septic shock.The conditions that can be treated in accordance with the presentdisclosure include, but are not limited to viral infections, bacterialinfections, chronic inflammatory disorders, acute inflammatorydisorders, and cancers. Preferably, the condition to be treated includesa bacterial infection, a viral infection, or a cancer immunotherapy.Cancer immunotherapy can include cervical cancers such as thoseresulting from an infection of the cervix with human papillomavirus.

Viral infections can include those caused by ebola, influenza, SARS,Noro (gastro), or Zika. Viral infections can include viral respiratoryinfections (e.g., of the nose, throat, upper airways, or lungs) such aspneumonia, laryngotracheobronchitis, bronchiolitis. Viral infections caninclude viral gastrointestinal infections such as gastroenteritis causedby a norovirus or rotavirus. Viral infections can include viral liverinfections such as hepatitis. Viral infections can include viral nervoussystem infections such as encephalitis caused by rabies or West Nile.Viral infections include warts and/or infections caused by humanpapilloma virus (HPV). Viral infections can include infections thatcause cancer such as infections caused by Epstein-Barr virus, HepatitisB, Hepatitis C, Herpesvirus 8, or Human papillomavirus. Symptoms ofviral infections can include fever, muscle aches, coughing, sneezing,runny nose, headache, chills, diarrhea, vomiting, rash, or weakness.

Bacterial infections can include pneumonia, meningitis, food poisoning,and bacterial skin infections such as those caused by Staphylococcus orStreptococcus, cellulitis, folliculitis, impetigo, and boils. Bacterialinfections (e.g., by food poisoning) can include infections caused byEscherichia coli (E. coli), Campylobacter jejuni, Clostridium botulinum,Listeria monocytogenes, salmonella, and Vibrio. Bacterial infections caninclude bacterial meningitis, Otitis media, urinary tract infection, andrespiratory tract infections such as sore throat, bronchitis, sinusitis,and pneumonia. Symptoms of bacterial infections can include nausea,vomiting, diarrhea, fever, chills, and abdominal pain.

In some aspects, the methods described herein are used to treat patientswith disorders arising from dysregulated cytokine, enzymes and/orinflammatory mediator production, stability, secretion,posttranslational processing. Examples of cytokines that may bedysregulated include interleukins 1, 2, 6, 8, 10, 12, 17, 22 and 23along with tumor necrosis factor alpha and interferons alpha, beta andgamma. Examples of inflammatory mediators that may be dysregulatedinclude nitric oxide, prostaglandins and leukotrienes. Examples ofenzymes include cyclo-oxygenase, nitric oxide synthase andmatrixmetalloprotease.

Examples of inflammatory conditions relevant to the technology include,but are not limited to, sepsis, septic shock, endotoxic shock,exotoxin-induced toxic shock, gram negative sepsis, toxic shocksyndrome. Inflammatory conditions can include those experienced byimmunosuppressed individuals, and can also include “superbugs”,including bacterial and viral strains resistant to current therapeutics.

2. Subjects

Suitable subjects to be treated according to the present disclosureinclude mammalian subjects. Mammals according to the present disclosureinclude, but are not limited to, human, canine, feline, bovine, caprine,equine, ovine, porcine, rodents, lagomorphs, primates, and the like, andencompass mammals in utero. Subjects may be of either gender and at anystage of development.

3. Administration and Dosing

Compounds or compositions of the present disclosure can be administeredto a subject in a therapeutically effective amount.

Compounds or compositions of the present disclosure can be administeredby any suitable route in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. An effective dosage is typically in the range of about 0.001to about 100 mg per kg body weight per day, preferably about 0.01 toabout 30 mg/kg/day, in single or divided doses. Depending on age,species and condition being treated, dosage levels below the lower limitof this range can be suitable. In other cases, still larger doses can beused without side effects. Larger doses can also be divided into severalsmaller doses, for administration throughout the day.

Pharmaceutical Compositions

For the treatment of the conditions referred to above, the compounds ofdescribed herein can be administered as follows:

Oral Administration

Compounds or compositions of the present disclosure can be administeredorally, including by swallowing, so that the compound enters thegastrointestinal tract, or absorbed into the blood stream directly fromthe mouth (e.g., buccal or sublingual administration).

Suitable compositions for oral administration include solid formulationssuch as tablets, lozenges and capsules, which can contain liquids, gels,or powders. Compositions for oral administration may be formulated asimmediate or modified release, including delayed or sustained release,optionally with enteric coating.

Liquid formulations can include solutions, syrups and suspensions, whichcan be used in soft or hard capsules. Such formulations can include apharmaceutically acceptable carrier, for example, water, ethanol,polyethylene glycol, cellulose, or an oil. The formulation can alsoinclude one or more emulsifying agents and/or suspending agents.

In a tablet dosage form the amount of a compound of formula (I) presentcan be from about 0.05% to about 95% by weight, such as from about 2% toabout 50% by weight of the dosage form. In addition, tablets may containa disintegrant, comprising from about 0.5% to about 35% by weight, suchas from about 2% to about 25% of the dosage form. Examples ofdisintegrants include methyl cellulose, sodium or calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropylcellulose, or starch.

Suitable lubricants, for use in a tablet, can be present in amounts fromabout 0.1% to about 5% by weight. Lubricants can include calcium, zincor magnesium stearate, or sodium stearyl fumarate.

Suitable binders, for use in a tablet, include gelatin, polyethyleneglycol, sugars, gums, starch, hydroxypropyl cellulose and the like.Suitable diluents, for use in a tablet, include mannitol, xylitol,lactose, dextrose, sucrose, sorbitol, or starch.

Suitable surface active agents and glidants, for use in a tablet, may bepresent in amounts from about 0.1% to about 3% by weight. Surface activeagents and glidants can include polysorbate 80, sodium dodecyl sulfate,talc, or silicon dioxide.

Parenteral Administration

Compounds and compositions of the present disclosure can be administereddirectly into the blood stream, muscle, or internal organs. Suitablemethods for parenteral administration can include intravenous,intra-muscular, subcutaneous intraarterial, intraperitoneal,intrathecal, or intracranial. Suitable devices for parenteraladministration include injectors (including needle and needle-freeinjectors) and infusion methods.

Compositions for parenteral administration can be formulated asimmediate or modified release, including delayed or sustained release.

Most parenteral formulations are aqueous solutions containingexcipients, including salts, buffering agents and carbohydrates.

Parenteral formulations can also be prepared in a dehydrated form (e.g.,by lyophilization) or as sterile non-aqueous solutions. Theseformulations can include water. Solubility-enhancing agents can also beused in preparation of parenteral solutions.

Topical Administration

Compounds and compositions of the present disclosure can be administeredtopically to the skin or transdermally. Formulations for this topicaladministration can include lotions, solutions, creams, gels, hydrogels,ointments, foams, implants, patches and the like. Pharmaceuticallyacceptable carriers for topical administration formulations can includewater, alcohol, mineral oil, glycerin, polyethylene glycol and the like.Topical administration can be performed by electroporation,iontophoresis, or phonophoresis.

Compositions for topical administration can be formulated as immediateor modified release, including delayed or sustained release.

Combinations and Combination Therapy

The compounds and compositions of the present disclosure can be used,alone or in combination with other pharmaceutically active compounds, totreat conditions such as those previously described above. Thecompound(s)/composition(s) of the present disclosure and otherpharmaceutically active compound(s) can be administered simultaneously(either in the same dosage form or in separate dosage forms) orsequentially. Accordingly, in one aspect, the present disclosureincludes methods for treating a condition by administering to thesubject a therapeutically-effective amount of one or more compounds ofthe present disclosure and one or more additional pharmaceuticallyactive compounds.

In another aspect, there is provided a pharmaceutical compositioncomprising one or more compounds of the present disclosure, one or moreadditional pharmaceutically active compounds, and a pharmaceuticallyacceptable carrier.

In another aspect, the one or more additional pharmaceutically activecompounds is one or more anti-inflammatory drugs, anti-atheroscleroticdrugs, immunosuppressive drugs, immunomodulatory drugs, cytostaticdrugs, anti-proliferative agents, angiogenesis inhibitors, kinaseinhibitors, cytokine blockers, or inhibitors of cell adhesion molecules.

Compounds and compositions of the present disclosure can also be used incombination with other therapeutic reagents that are selected for theirtherapeutic value for the condition to be treated. In general, thecompounds and compositions described herein and, in aspects wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and, because ofdifferent physical and chemical characteristics, are optionallyadministered by different routes. The initial administration isgenerally made according to established protocols, and then, based uponthe observed effects, the dosage, modes of administration and times ofadministration subsequently modified. In certain instances, it isappropriate to administer a compound of formula (I) as described hereinin combination with another therapeutic agent. By way of example only,if one of the side effects experienced by a patient upon receiving acompound of formula (I) is rash, then it is appropriate to administer ananti-histamine agent in combination with the initial therapeutic agent.Or, by way of example only, the therapeutic effectiveness of a compoundof formula (I) is enhanced by administration of another therapeuticagent (which also includes a therapeutic regimen) that also hastherapeutic benefit. Regardless of the disease, disorder or conditionbeing treated, the overall benefit experienced by the patient is eithersimply additive of the two therapeutic agents or the patient experiencesa synergistic benefit.

Therapeutically effective dosages vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically effective dosages of drugs and other agents for use incombination treatment regimens are documented methodologies. Combinationtreatment further includes periodic treatments that start and stop atvarious times to assist with the clinical management of the patient. Inany case, the multiple therapeutic agents (one of which is a compound offormula (I)) are administered in any order, or even simultaneously. Ifsimultaneously, the multiple therapeutic agents are optionally providedin a single, unified form, or in multiple forms (by way of example only,either as a single pill or as two separate pills).

In some aspects, one of the therapeutic agents is given in multipledoses, or both are given as multiple doses. If not simultaneous, thetiming between the multiple doses optionally varies from more than zeroweeks to less than twelve weeks.

In addition, the combination methods, compositions and formulations arenot to be limited to the use of only two agents, the use of multipletherapeutic combinations are also envisioned. It is understood that thedosage regimen to treat, prevent, or ameliorate the condition(s) forwhich relief is sought, is optionally modified in accordance with avariety of factors. These factors include the disorder from which thesubject suffers, as well as the age, weight, sex, diet, and medicalcondition of the subject. Thus, the dosage regimen actually used canvary widely, in some aspects, and therefore can deviate from the dosageregimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein are optionally a combined dosage form or in separatedosage forms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy areoptionally also administered sequentially, with either agent beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen optionally calls for sequentialadministration of the active agents or spaced-apart administration ofthe separate active agents. The time period between the multipleadministration steps ranges from, a few minutes to several hours,depending upon the properties of each pharmaceutical agent, such aspotency, solubility, bioavailability, plasma half-life and kineticprofile of the pharmaceutical agent. Circadian variation of the targetmolecule concentration is optionally used to determine the optimal doseinterval.

Compounds represented by formula (I) and a composition having a compoundrepresented by formula (I) can be used (e.g., administered) incombination with drugs from the following classes: NSAIDs,immunosuppressive drugs, immunomodulatory drugs, cytostatic drugs,anti-proliferative agents, angiogenesis inhibitors, biological agents,steroids, vitamin D3 analogs, retinoids, other kinase inhibitors,cytokine blockers, corticosteroids and inhibitors of cell adhesionmolecules. Where a subject is suffering from or at risk of sufferingfrom atherosclerosis or a condition that is associated withatherosclerosis, a compound represented by formula (I) or a compositionhaving a compound represented by formula (I) described herein isoptionally used together with one or more agents or methods for treatingatherosclerosis or a condition that is associated with atherosclerosisin any combination. Examples of therapeutic agents/treatments fortreating atherosclerosis or a condition that is associated withatherosclerosis include, but are not limited to any of the following:torcetrapib, aspirin, niacin, HMG CoA reductase inhibitors (e.g.,atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin andsimvastatin), colesevelam, cholestyramine, colestipol, gemfibrozil,probucol and clofibrate.

Where a subject is suffering from or at risk of suffering from aninflammatory condition, a compound represented by formula (I) or acomposition having a compound represented by formula (I) describedherein is optionally used together with one or more agents or methodsfor treating an inflammatory condition in any combination. Examples oftherapeutic agents/treatments for treating an autoimmune and/orinflammatory condition include, but are not limited to any of thefollowing: corticosteroids, nonsteroidal antiinflammatory drugs (NSAID)(e.g. ibuprofen, naproxen, acetaminophen, aspirin, Fenoprofen (Nalfon),Flurbiprofen (Ansaid), Ketoprofen, Oxaprozin (Daypro), Diclofenac sodium(Voltaren), Diclofenac potassium (Cataflam), Etodolac (Lodine),Indomethacin (Indocin), Ketorolac (Toradol), Sulindac (Clinoril),Tolmetin (Tolectin), Meclofenamate (Meclomen), Mefenamic acid (Ponstel),Nabumetone (Relafen), Piroxicam (Feldene), cox-2 inhibitors (e.g.,celecoxib (Celebrex))), immunosuppressants (e.g., methotrexate(Rheumatrex), leflunomide (Arava), azathioprine (Imuran), cyclosporine(Neoral, Sandimmune), tacrolimus and cyclophosphamide (Cytoxan), CD20blockers (Rituximab), Tumor Necrosis Factor (TNF) blockers (e.g.,etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira)),Abatacept (CTLA4-Ig) and interleukin-1 receptor antagonists (e.g.Anakinra (Kineret), interleukin 6 inhibitors (e.g., Actemra),interleukin 17 inhibitors (e.g., AIN457), Janus kinase inhibitors (e.g.,Tasocitinib), syk inhibitors (e.g. R788), chloroquine and itsderivatives.

For use in cancer and neoplastic diseases a compound represented byformula (I) or a composition having a compound represented by formula(I) described herein is optionally used together with one or more of thefollowing classes of drugs: wherein the anti-cancer agent is an EGFRkinase inhibitor, MEK inhibitor, VEGFR inhibitor, anti-VEGFR2 antibody,KDR antibody, AKT inhibitor, PDK-1 inhibitor, PI3K inhibitor, c-kit/Kdrtyrosine kinase inhibitor, Bcr-Abl tyrosine kinase inhibitor, VEGFR2inhibitor, PDGFR-beta inhibitor, KIT inhibitor, Flt3 tyrosine kinaseinhibitor, PDGF receptor family inhibitor, Flt3 tyrosine kinaseinhibitor, RET tyrosine kinase receptor family inhibitor, VEGF-3receptor antagonist, Raf protein kinase family inhibitor, angiogenesisinhibitor, Erb2 inhibitor, mTOR inhibitor, IGF-1R antibody, NFkBinhibitor, proteosome inhibitor, chemotherapy agent, or glucosereduction agent.

Aspects

Clause 1. A compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein:Q is fluoro, chloro, bromo, or iodo;each of s, b, and n is independently an integer from about 10 to about100; andeach of v, j, p, z, q, x and m is independently an integer from 1 toabout 20.Clause 2. The compound of clause 1, wherein s is an integer from about20 to about 40.Clause 3. The compound of clauses 1 or 2, wherein s is an integer fromabout 25 to about 35.Clause 4. The compound of any of clauses 1-3, wherein b is an integerfrom about 30 to about 60.Clause 5. The compound of any of clauses 1-4, wherein b is an integerfrom about 40 to about 50.Clause 6. The compound of any of clauses 1-5, wherein n is an integerfrom about 30 to about 60.Clause 7. The compound of any of clauses 1-6, wherein n is an integerfrom about 50 to about 60.Clause 8. The compound of any of clauses 1-7, wherein m is an integerfrom about 1 to about 10.Clause 9. The compound of any of clauses 1-8, wherein m is an integerfrom about 5 to about 10.Clause 10. The compound of any of clauses 1-9, wherein Q is chloro.Clause 11. The compound of any of clauses 1-10, wherein x is an integerfrom about 5 to about 15.Clause 12. The compound of any of clauses 1-11, wherein x is the integer7, 11, or 15.Clause 13. The compound of any of clauses 1-12, wherein a ratio of theinteger n to the integer m is from about 1:1 to about 100:1.Clause 14. The compound of any of clauses 1-13, wherein the ratio of theinteger n to the integer m is from about 5:1 to about 15:1.Clause 15. The compound of any of clauses 1-14, wherein the compound isrepresented by formula (II):

or a pharmaceutically acceptable salt thereof, wherein:Q is fluoro, chloro, bromo, or iodo;each of s, b, and n is independently an integer from about 10 to about100; andeach of x and m is independently an integer from 1 to about 20.Clause 16. The compound of clause 15, wherein s of formula (II) is aninteger from about 20 to about 40.Clause 17. The compound of clauses 15 or 16, wherein s of formula (II)is an integer from about 25 to about 35.Clause 18. The compound of any of clauses 15-17, wherein b of formula(II) is an integer from about 30 to about 60.Clause 19. The compound of any of clauses 15-18, wherein b of formula(II) is an integer from about 40 to about 50.Clause 20. The compound of any of clauses 15-19, wherein n of formula(II) is an integer from about 30 to about 60.Clause 21. The compound of any of clauses 15-20, wherein n of formula(II) is an integer from about 50 to about 60.Clause 22. The compound of any of clauses 15-21, wherein m of formula(II) is an integer from about 1 to about 10.Clause 23. The compound of any of clauses 15-22, wherein m of formula(II) is an integer from about 5 to about 10.Clause 24. The compound of any of clauses 15-23, wherein Q is chloro.Clause 25. The compound of any of clauses 15-24, wherein x of formula(II) is an integer from about 5 to about 15.Clause 26. The compound of any of clauses 15-25, wherein the compound isrepresented by formula (III):

or a pharmaceutically acceptable salt thereof, wherein x is an integerfrom about 5 to about 15.Clause 27. The compound of any of clauses 15-26, wherein x is theinteger 7, 11, or 15.Clause 28. A composition comprising:

the compound of any of clauses 15-27; and

a compound represented by formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:each of s and b of formula (IV) is independently an integer from about10 to about 100;v of formula (IV) is an integer from about 1 to about 20;R¹ is —O— or —NH—; andR² is —CH₃, biotin, pyridyl disulfide, dopa, thiolactone, or adamantyl.Clause 29. The composition of clause 28, wherein s of formula (IV) is aninteger from about 25 to about 35.Clause 30. The composition of clauses 28 or 29, wherein b of formula(IV) is an integer from about 40 to about 50.Clause 31. The composition of any of clauses 28-30, wherein v of formula(IV) is 2.Clause 32. The composition of any of clauses 28-31, wherein R² is

Clause 33. The composition of any of clauses 28-32, wherein the compoundrepresented by formula (IV) is one or more of:

wherein s of formula (IV) is an integer from about 25 to about 35 and bof formula (IV) is an integer from about 40 to about 50.Clause 34. The composition of any of clauses 28-33, wherein thecomposition has a 3-dimensional structure that is a nanoworm or nanorod.Clause 35. The composition of any of clauses 28-34, wherein thecomposition is a nanorod having an aspect ratio from about 10:1 to about1000:1.Clause 36. The composition of any of clauses 28-35, wherein thecomposition is a nanorod having a diameter from about 10 nm to about 20nm and a length from about 1 micron to about 2 microns.Clause 37. The composition of any of clauses 28-36, wherein a ratio ofthe compound represented by formula (I) to the compound represented byformula (IV) is from about 0.01:1 to about 1:0.01.

EXAMPLES Experimental

Measurements

Nuclear Magnetic Resonance (NMR). All NMR spectra were recorded on aBruker DRX 400 or 500 MHz spectrometer using an external lock (CDCl₃ orDMSO-d₆) and referenced to the residual nondeuterated solvent (CHCl₃ orDMSO).

Size Exclusion Chromatography (SEC) and Triple Detection-Size ExclusionChromatography (TD-SEC). Analysis of the molecular weight distributionsof the polymers were determined using a Polymer Laboratories GPC50 Plusequipped with differential refractive index detector. Absolute molecularweights of polymers were determined using a Polymer Laboratories GPC50Plus equipped with dual angle laser light scattering detector,viscometer, and differential refractive index detector. High performanceliquid chromatography (HPLC) grade N,N-dimethylacetamide (DMAc,containing 0.03 wt % LiCl) was used as the eluent at a flow rate of 1.0mL/min. Separations were achieved using two PLGel Mixed B (7.8×300 mm)SEC columns connected in series and held at a constant temperature of50° C. The triple detection system was calibrated using a 5 mg/mL 110 Kpolystyrene (PSTY) standard. Samples of known concentration were freshlyprepared in DMAc+0.03 wt % LiCl and passed through a 0.45 μm PTFEsyringe filter prior to injection. The absolute molecular weights anddn/dc values were determined using Polymer Laboratories Multi Cirrussoftware based on the quantitative mass recovery technique.

Transmission Electron Microscopy (TEM). The nanostructure appearance ofthe polymer lattices was analyzed using a JEOL-1010 transmissionelectron microscope utilizing an accelerating voltage of 100 kV withspot size 5 at ambient temperature. A typical TEM grid preparation wasas follows: the nanostructure samples were diluted with Milli-Q water at34° C. to approximately 0.05 wt %. A formvar preheated (34° C.) copperTEM grid was then dipped in the diluted solution, blotted the excesssolution by filter paper and then dried at 34° C.

Matrix Assisted Laser Desorption Ionisation Time of Flight MassSpectroscopy (MALDI-TOF). A Mass Spectrometry Spectrum was recordedusing a Bruker autoflex III smartbeam operated in reflection mode. Ionswere accelerated at a potential of 20 kV with a nitrogen laser emittingat 337 nm. The polymer solution concentrations were 1 mg/mL intetrahydrofuran (THF), for sodium trifluoroacetate (NaTFA) 1 mg/mL inTHF and for DCTB (T-2-(3-(4-t-Butyl-phenyl)-2-methyl-2-propenylidene)malononitrile) 10 mg/ml. To prepare the sample for measurement, 20 μLpolymer solution, 20 μL DCTB solutions and 2 μL NaTFA solution weremixed in an Eppendorf tube, vortexed and centrifuged. 1 μL solution wasplaced on the sample plate spot, dried at ambient condition and thenproceeded the measurement.

UV-Vis spectrometer. UV-Vis absorption spectra were recorded on a UV-VisCary 4000 spectrophotometer at 25° C.

Confocal Microscopy. The confocal microscopy images of the fluorescenceprobe labeled nanorods were dispersed in Milli-Q water at 20 mg/mL. 5 SLof each sample was dropped on a glass slide. Confocal microscopy imageswere taken using a Confocal LSM Zeiss 710 Laser Scanning Microscope(inverted) with an oil-immersion objective (1.40 Oil DIC M27/63×). Twoexcitation wavelengths at 488 and 561 nm were used for Oregon green 488and SAv-DyLight 550, respectively.

Dynamic Light Scattering (DLS). Dynamic Light Scattering measurementswere performed using a Malvern Zetasizer Nano Series 3000HS running DTSsoftware operating a 4 mW He—Ne laser at 633 nm. Analysis was performedat an angle of 173°. The sample refractive index (RI) was set at 1.59for polystyrene. The dispersant viscosity and RI for water were set to0.4071 mP (70° C.) and 1.33 Ns/m2, respectively. The number averagehydrodynamic particle size and particle size distribution (PSD) werereported. The PSD was used to describe the width of the particle sizedistribution. It was calculated from a cumulate analysis of the DLSmeasured intensity autocorrelation function and related to the standarddeviation of the hypothetical Gaussian distribution (i.e.,PSDDLS=σ²/ZD², where σ is the standard deviation and ZD is the Z averagemean size).

For determination of the lower critical solution temperature (LCST) ofall PNIPAM MacroCTAs, the polymer MacroCTAs were dissolved in Milli-Qwater in an ice bath at a concentration of 5 mg/mL or 53.8 mg/mL, andSDS was added at a concentration of 0.21 mg/mL or 2.23 mg/mL,respectively. The solution was then filtered using a 0.45 μm cellulosesyringe filter directly into a DLS cuvette. The polymer solution wascooled to 5° C. and the cuvette placed in DLS spectrometer. Themeasurement was carried out by slowly increasing the temperature from 5to 70° C. at a ramp rate controlled by the SOP (standard operatingprocedure) software.

Materials:

Synthesis of Functional Polymer Nanostructure Materials

Unless otherwise stated, all chemicals were used as received. Thesolvents used were of either HPLC or AR grade; these includeddichloromethane (DCM; Aldrich AR grade), dimethylformamide (DMF;Aldrich, AR grade) and tetrahydrofuran (THF; Labscan, HPLC grade), DMSO(Aldrich, 99.9%). Activated basic alumina (Aldrich: Brockmann I,standard grade, ˜150 mesh, 58 A), Milli-Q water (Biolab, 18.2 M=m),sodium dodecyl sulphate (SDS; Aldrich, 99%), triethylamine (TEA; Fluka,99%), N,N′-dicyclohexylcarbodiimide (DCC, Aldrich, 99%),N-hydroxysuccinimide (NHS, Aldrich, 98%), ethanolamine (Aldrich, >99%),4-(dimethylamino)pyridine (DMAP, Merck, 99%), copper(II) sulfate(Aldrich, 99%), Lascorbic acid (Aldrich, 99%), 1-butanethiol (Aldrich,99%), propargyl alcohol (Aldrich, 99%), sodium azide (Aldrich, 99.5%),methacryloyl chloride (Fluka, 97%), 3-chloro-1-propanol (Aldrich, 98%),poly(ethylene glycol) mono methyoxyl ether-2000 (mPEG, Aldrich),p-toluenesulfonyl chloride (Aldrich, >99%), β-cyclodextrin(Sigma, >97%), allylamine (Aldrich, 98%), Aldrithiol™-2 (DPDS, Aldrich,98%), 2-mercaptoethanol (Merck, >98%), dopamine hydrochloride (Sigma),DL-homocysteine thiolactone hydrochloride (TIa, Aldrich, >99%), biotin(Sigmal-Aldrich, >99%), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDC HCl, Fluka, >98%), L-glutathione reduced(Sigma-Aldrich, >98%), streptavidin from Streptomyces avidinii (SAv,Sigma), streptavidin DyLight 550 conjugated (Pierce), Oregon GreenR 488maleimide (Molecular ProbesR), carbon disulfide (Aldrich, >99.9%),2-bromo-2-methylpropionic acid (Aldrich, 98%) andmethyl-2-bromopropionate (MBP; Aldrich, 98%) were used as received.Styrene (STY: Aldrich, >99%) was passed through a basic alumina columnto remove inhibitor. N-isopropylacrylamide (NIPAM: Aldrich, 97%) wasrecrystallized from (n-hexane/toluene, 9/1, v/v), andazobisisobutyronitrile (AIBN, Riedel-de Haen) was recrystallized frommethanol twice prior to use.

RAFT agent methyl 2-(butylthiocarbonothioylthio)propanoate (MCEBTTC) wassynthesized according to the previous procedure. (C. N. Urbani, M. J.Monteiro, Macromolecules, 2009, 42, 3884-3886.)

Synthesis of Carboxylic Acid Functional RAFT Agent (Acid-RAFT)

Potassium phosphate tribasic (16.6 g, 0.0782 mol) was dissolved in 130mL acetone in a 500 mL round bottom flask. This mixture was keptstirring for 5 h to make a light yellow suspension. To this mixture,1-butanethiol (8.0 mL, 0.0742 mol) was added and stirred for 1 h. Carbondisulfide (9.1 mL, 0.151 mol) was then added dropwise to this stirredmixture and stirred for 2 h at 0.5° C. (in an ice bath). 2-Bromo-2methylpropionic acid (11.7 g, 0.07 mol) was added to the mixture understirring, and the mixture was allowed to react overnight at roomtemperature (23° C.). The solid was isolated by filtration, and thesolvent volume reduced by using rotary evaporation. The residue was thendiluted by cold 10% HCl solution (4×50 mL) and stirred at roomtemperature overnight. This solution was then extracted twice withn-Hexane, dried over anhydrous MgSO₄, filtered, and solvent removed byrotary evaporation. The residual yellow solid was purified by columnchromatography (petroleum spirit/ethyl acetate: 3/2 on silica, Rf=0.51).The solvent was then removed by rotary evaporation, the compounddissolved in n-Hexane, and kept in a freezer to crystallize. The productwas filtered, dried under high vacuum for 24 h, producing a yield of61%. ¹H NMR (CDCl₃, 298K, 300 MHz): ppm 3.27 (t, 2H; J=7.38 Hz;CH₃CH₂CH₂CH₂S—), 1.70 (s, 6H; (CH₃)₂—), 1.64 (m, 2H, J=8.94 Hz;CH₃CH₂CH₂CH₂S—), 1.41 (m, 2H; J=7.29 Hz; CH₃CH₂CH₂CH₂S—), 0.90 (t, 3H,J=7.26 Hz; CH₃CH₂CH₂CH₂S—); 13C NMR (CDCl₃, 298K, 75 MHz): 228.3, 128.9,55.6, 36.7, 29.8, 25.2, 22.1, 13.6.

Synthesis of Pyridyl Disulfide Functional RAFT Agent (PDS-RAFT)

As shown in Scheme 2, RAFT-acid (2.52 g, 0.01 mol), hydroxyethylpyridyldisulfide (2.0 g, 0.011 mol), DCC (4.12 g, 0.02 mol) and DMAP(0.112 g, 9.18×10−4 mol) were dissolved in 50 mL of DCM which was cooledto 0° C. with an ice bath. The reaction mixture was allowed to warm toroom temperature and stirred for 24 h. DCM was removed by rotaryevaporation. The residue was redispersed in diethyl ether, filtered. Thefiltrate was concentrated to a viscous residual and purified by silicacolumn chromatography (¼ petroleum spirit/ethyl acetate), yield: 59.4%.

Synthesis of Dopamine Functional RAFT Agent (Dopa-RAFT)

As shown in Scheme 3, RAFT-acid (3.0 g, 0.012 mol), NHS (1.5 g, 0.013mol) and DCC (2.67 g, 0.013 mol) were dissolved in 50 mL of DCM whichwas cooled to 0° C. with an ice bath. The reaction mixture was warmed upto room temperature and stirred for 2 h. The reaction was monitored byTLC to get full conversion to RAFT-active ester. The mixture was thenfiltered to another round bottom flask with stirrer. Dopaminehydrochloride (2.0 g, 0.011 mol) and TEA (1.7 mL, 0.012 mol) weredissolved in 10 mL DMF and added to the above RAFT-active esterdropwise. The reaction mixture was stirred for another 24 h. The colorof reaction mixture turned brown. 50 mL of DCM was added to the reactionmixture. The mixture was then washed with 0.1N HCl solution followed byMilli-Q water. The color of the DCM phase turned to yellow. The DCMphase was dried over MgSO₄, filtered and concentrated. The filtrate wasconcentrated to a viscous residual and purified by silica columnchromatography (1/1 petroleum spirit/ethyl acetate), yield: 44.3%.

Synthesis of Biotin Functional RAFT Agent (Biotin-RAFT)Synthesis of Hydroxyl Functional RAFT (RAFT-OH)

As shown in Scheme 4, RAFT-acid (1.75 g, 6.9×10−3 mol), NHS (0.95 g,8.3×10−3 mol) and DCC (1.72 g, 8.3×10−3 mol) were dissolved in 30 mL ofDCM which was cooled to 0° C. with an ice bath. The reaction mixture waswarmed up to room temperature and stirred for 2 h. The reaction wasmonitored by TLC to get full conversion to RAFT-active ester. Themixture was then filtered to another round bottom flask with stirrer.Ethanolamine (0.4 g, 6.5×10−3 mol) was dissolved in 10 mL DMF and addedto the above RAFT-active ester dropwise. The reaction mixture wasstirred for another 24 h. The mixture was filtered, concentrated to aviscous residual and purified by silica column chromatography (½petroleum spirit/ethyl acetate), yield: 55.0%.

Synthesis of Biotin Functional RAFT (Biotin-RAFT)

As shown in Scheme 5, RAFT-OH (1.10 g, 3.73×10−3 mol), biotin (0.91 g,3.73×10−3 mol), EDC.HCl (1.42 g, 7.45×10−3 mol) and DMAP (45.5 mg,3.73×10-3 mol) were dissolved in 20 mL of DMF which was cooled to 0° C.with an ice bath. The reaction mixture was warmed up to room temperatureand stirred for 48 h. The reaction mixture was then diluted with 100 mLDCM and washed by deionized water for five times. The DCM phase was thendried over MgSO₄, filtered, concentrated to a viscous residual andpurified by silica column chromatography (⅛ methanol/DCM), yield: 69.6%.

Synthesis of Functional Poly(NIPAM) Macro-CTA

All the functional poly(NIPAM) macro-CTAs were synthesized by reversibleaddition-fragmentation chain-transfer polymerization (RAFTpolymerization) in DMSO at 60° C. The feeding ratio of NIPAM/RAFTagent/AIBN was kept as 44/1/0.1 for all the different functional RAFTagents. The ratio of DMSO to NIPAM was kept as 2/1 (v/w). Typically, (10g, 8.85×10−2 mol), methyl-RAFT (0.58 g, 2.0×10−3 mol) and AIBN (3.3 mg,2.0×10−4 mol) were dissolved in 20 mL of DMSO. The mixture was purgedwith Argon for 30 min then heated at 60° C. for 16 h. The reaction wasstopped by cooling to 0° C. in an ice bath and exposed to air. Thesolution was then diluted with 500 mL of DCM and washed with Milli-Qwater (5×100 mL). The DCM phase was then dried over anhydrous MgSO₄,filtered and concentrated by rotary evaporation. The polymer wasrecovered by precipitation into large excess of diethyl ether (500 mL),isolated by filtration, and then dried under vacuum for 24 h at roomtemperature to get a yellow powder product (yield 45%). The conversionwas 96% as determined from ¹H NMR spectroscopy.

Table 1 summarizes the data of the functional poly(NIPAM) macro-CTAs.

TABLE 1 Repeating Macro- Functional M_(n) M_(n) NIPAM CTA group (SEC)PDI (NMR) units 1 Methyl- 4300 1.09 5340 45 2 Pyridine 4300 1.09 5510 45disulfide-(PDS-) 3 Dopamine-(Dopa-) 5900 1.12 7860 55 4 Biotin- 42001.08 5490 44RAFT-Mediated Emulsion Polymerization of Styrene with FunctionalPoly(NIPAM) Macro-CTAs in Water

The polymerizations were as follows: The cumulative total mass of thepoly(NIPAM) macro-CTAs was (0.35 g). The other components present in thereaction mixture were styrene (0.35 g); SDS (14.5 mg), AIBN (1.2 mg),Milli-Q water (6.25 g). Dopa-poly(NIPAM) macro-CTA 3 (0.105 g, 1.33×10−5mol), Biotin-poly(NIPAM) macro-CTA 4 (0.07 g, 1.66×10−5 mol) and SDS(7.25 mg, 5×10−5 mol) were dissolved in cold water (3.125 g) in aSchlenk tube. The mixture was deoxygenated by purging with Argon for 15mins. AIBN (0.6 mg, 3.7×10−6 mol) was dissolved in styrene (0.175 g,1.7×10−3) and then the solution was injected into the Schlenk flask. Themixture was then purged with Argon for another 10 mins in an ice bathbefore heating up to 70° C. for 3.5 h. The reaction was stopped byexposed the air at 70° C. The polymer emulsion was then characterized bySEC, ¹H NMR and DLS. Data are shown in Table 2.

TABLE 2 Dh RXN Macro-CTA Conv. % Mn (SEC) PDI Mn (NMR) Mn (Theo) (nm)PSD 1 0.4 0.6 67 7100 1.18 8200 8410 144 0.24 (Biotin) (Dopa) 2 0.4 0.658 6030 1.23 8100 8000 161 0.03 (PDS) (Dopa)

Furthermore, transmission electron microscope images of the 60%Dopa-functional/40% Biotin-functional compositions illustrate that thethree dimensional structure of the composition is nanoworm. ¹H NMRindicated an average of 45 repeating NIPAM units and 29 to 30 repeatingPSTY units in each of the diblock polymers.

Coating of Nanoworms to the Surface

Glass slips (and silicon wafer) were washed successively with 10% HClaq, acetone and methanol. The slips were then dry under nitrogen flow.To four 50 ml plastic vials (a, b, c and d), 10 mg of 60% Dopa- and 40%Biotin functional nanoworms were added in each vial and dispersed in 4ml tris(hydroxymethyl)aminomethane (Tris) solution (10 mM, pH=8.5) andrehydrated for 20 min. Glass slips and silicon wafer were added. Thendifferent amounts (1, 60, 120, 240 μL) of dopamine solution (33 mg/ml)were added to a, b, c and d vials, respectively. The mixture was thenshaken for 4 hours. The silicon wafer was taken out and washed withwater and dried for SEM images. The glass slips were washed with waterand then immersed in 0.5 ml of SAv-DyLight 550 protein solution for 1min. The slips were then washed with water again and kept in water forfluorescence microscopy.

Fluorescence images (a-d) of 60% Dopa- and 40% Biotin functionalnanoworms on the glass slips with different amount of free dopamineaddition ((a) 0 mg/ml, (b) 0.5 mg/ml, (a) 1.0 mg/ml and (e) 2.0 mg/ml)and then treated with SAv-550 solution showed that the incorporation ofthe biotin was near quantitative on the surface of the worms.

SEM of silicon wafer (e-h) coated with of 60% Dopa- and 40% Biotinfunctional nanoworms showed that 4 hours of coating and 1.0 mg/ml offree dopamine gave the best coating to both glass slips and siliconwafer.

Synthesis of Maleimide Functional Cationic Polymer

Synthesis of Furan-Protected Maleimide Initiator

The initiator was synthesized according the literature (Geng, et al., J.Am. Chem. Soc., 2007, 129 (49), pp 15156-15163). Synthesis offuran-protected maleimide poly-dimethylaminoEA (poly-DMAEA)

DMAEA 15 ml (0.1 mol), initiator 0.197 g (6.6×10−4 mol), CuCl₂ 8.8 mg(6.6×10−5 mol), Tris[2-(dimethylamino)ethyl]amine (Me6TREN) 61 mg(2.6×10−4 mol) were added in 7.5 ml of isopropanol and purged with Argonfor 30 min. Cu(0) (<425 μm) 12.6 mg was added under Argon. Thepolymerization was allowed at room temperature for 6.5 hours with 41%conversion. The polymerization mixture was then diluted with acetone,passed through neutral Al₂O₃ to remove copper, the solution wasconcentrated and precipitated in petroleum spirit for three times anddried under high vacuum to yield 3.5 g polymer. M_(n)=9740 from NMR.FIG. 1 is a ¹H nuclear magnetic spectrum of the polymer in deuteratedchloroform (CDCl₃). For the polymer shown in FIG. 1, n is the integer61.

Synthesis of Quaternanized Furan-Protected Maleimide PDMAEA

As shown in Scheme 6, poly-DMAEA was quaternized with methyl iodide and1-iodo-alkane with different chain lengths (as shown in Table 3).Poly-DMAEA was reacted with long chain iodo-alkane at 60° C. for 8 h.The solution was cooled to room temperature and the corresponding amountof iodomethane was added. The reaction was allowed to stir overnight atroom temperature. The reaction mixture was then precipitated in acetoneto give a pale yellow powder that was then dried under high vacuum.

TABLE 3 Mass in Density Volume Ratio MW mol grams (g/ml³) (mL) Polymer APoly- 1 143 0.002797 0.4 DMAEA 1-iodooctane 0.1 240.13 0.00028 0.0671691.33 0.0505 Iodomethane 0.9 142 0.002517 0.357483 2.28 0.1568 dioxane 3Polymer B Poly- 1 143 0.002797 0.4 DMAEA 1-iodo- 0.1 296.23 0.000280.082862 1.2 0.0691 dodecane Iodomethane 0.9 142 0.002517 0.357483 2.280.1568 dioxane 3 Polymer C Poly- 1 143 0.002797 0.4 DMAEA 1- 0.1 352.340.00028 0.098557 1.121 0.0879 iodo- hexadecane Iodomethane 0.9 1420.002517 0.357483 2.28 0.1568 dioxane 3Deprotection of Quaternanized Furan-Protected Maleimide Poly-DMAEA

As shown in Scheme 7, quaternized poly-DMAEA was then dissolved in DMSO(0.2 g, in 4 ml) and then heated at 120° C. for 3 hours. The residualwas then precipitated in acetone to yield pale brown polymer material.The polymer was characterized by NMR to confirm the maleimide chain end.The percentage of long carbon chains was very close to the target amount(˜10%).

FIGS. 2A, 2B, and 2C illustrate ¹H NMR spectra of maleimide functionalquaternized-poly-DMAEA in D₂O. (n=61) (FIG. 2A) 10 mol % 1-iodooctane,(FIG. 2B) 10 mol % 1-iodododecane and (FIG. 2C) 10 mol %1-iodohexadecane.Conjugation of Maleimide Functional Cationic Polymers to the Dopa- andPDS-Functional Nanoworms

FIG. 3 is a scheme illustrating conjugation of maleimide functionalcationic polymer to Dopa- and PDS-functional nanoworms. Maleimidefunctional cationic polymer A, B, or C (12.7 mg each) was added to anEppendorf tube and 1 ml of water was added. After the polymer dissolved,a solution of polymer A, B, or C was added to another Eppendorf tubecomprising the nanoworms Dopa-(60%) and PDS-(40%) (20 mg of nanoworm).Then 10 μl TCEP solution (32.5 mg/ml) was added, the Eppendorf tube waswrapped with aluminum foil (protection from light), and the tube wasshaken overnight. The final product had the chemical structure shownbelow, where Nanoworm A had n=7, Nanoworm B had n=11, and Nanoworm C hadn=15.

Antibacterial TestingAntibacterial Testing for Maleimide Functional Cationic Polymer A, B andC in Solution

Experimental Set-Up

-   -   For Maleimide functional cationic polymer A, B and C a solution        of 5 mg/ml was made in water.    -   In a 24 well plate 500 μl of polymer solutions in water were        added in duplicates and 500 μl of water added to wells that        contain LB blank and E. coli.    -   500 μl of E. coli solution 1×10⁵ cells/ml was added to the wells        containing polymer in water. 500 μl LB added to blank wells.    -   Top of the plate was covered with parafilm before the lid was        placed on and then more parafilm was used to seal the edges to        stop solvent evaporation.    -   Plate was then placed in 37° C. incubator with shaking at 120        rpm for 14 hours.

The antibacterial activity of the polymers were measured based on theoptical density of the E. coli cultures. FIG. 4 is a bar graphillustrating the inhibitory effects of the polymers against E. colicultures. All three polymers showed great inhibition of bacterial growth(>90%).

Antibacterial Testing for Functional Cationic Nanoworms a, B and C inSolution.

Experiment Set-Up

-   -   For nanoworms A, B, and C, a solution of 5 mg/ml was made in        water.    -   In a 24 well plate 500 μl of nanoworm solutions in water were        added in duplicates and 500 μl of water added to wells that will        contain LB blank and E. coli.    -   500 μl of E. coli solution 1×10⁵ cells/ml was added to the wells        containing polymer in water. 500 μl LB added to blank wells.    -   Top of the plate was covered with parafilm before lid was placed        on and then more parafilm was used to seal the edges to stop        evaporation.    -   Plate was placed in 37° C. incubator with shaking at 120 rpm for        14 hours.    -   Could not measure E. coli by the usual method of measuring OD        due to the color of the solution.    -   E. coli growth was monitored by plating out nanoworm/E. coli        solutions on LB agar plates. Dilutions were done in LB and 20 μl        plated and left in the incubator O/N.

FIGS. 5A-5D are scanning electron microscope images showing theantibacterial activity of the cationic polymer nanoworms A, B, and Cagainst E. coli. (FIG. 5A) LB Blank and E. coli control, (FIG. 5B)nanoworms B, (FIG. 5C) nanoworms C and (FIG. 5D) nanoworms D all withdifferent dilution (102, 104, and 106) as indicated in the figure. Allnanoworms were able to kill the bacteria to almost 100%. Only one E.coli colony seen (circled in FIG. 5D). On the contrast, there are manyE. coli colonies seen on the +ve control plates (FIG. 5A). Thisindicated the cationic polymer nanoworms can efficiently kill almost allthe E. coli.

Overall, it has been shown that by using SAv-Biotin binding experimentand SEM, it has been demonstrated that the nanoworms can be effectivelycoated on the glass slips and silicon wafer. The maleimide functionalcationic polymers showed great inhibition of E. coli growth (>90%).Further conjugation of these maleimide functional nanoworms onto thePDS- and Dopa functional nanoworms retain the antibacterial properties.

Overall, compounds and compositions of the present disclosure canprovide an antimicrobial nanostructure capable of targeted binding tomicrobes and cell degeneration of the microbes. The ratiometric controlof functionality of compositions of the present disclosure provides anability to target and degenerate a wide range of microbes from bacteriato viruses.

Definitions

The term “pharmaceutically-acceptable” means suitable for use inpharmaceutical preparations, generally considered as safe for such use,officially approved by a regulatory agency of a national or stategovernment for such use, or being listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in animals, and moreparticularly in humans.

The term “pharmaceutically-acceptable salt” refers to a salt which mayenhance desired pharmacological activity. Examples ofpharmaceutically-acceptable salts include acid addition salts formedwith inorganic or organic acids, metal salts and amine salts. Examplesof acid addition salts formed with inorganic acids include salts withhydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid andphosphoric acid. Examples of acid addition salts formed with organicacids such as acetic acid, propionic acid, hexanoic acid, heptanoicacid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lacticacid, malonic acid, succinic acid, malic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid,o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethane-sulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methyl-bicyclo[2.2.2]oct-2-enel-carboxylic acid, gluco-heptonic acid,4,4′-methylenebis(3-hydroxy-2-naphthoic) acid, 3-phenylpropionic acid,trimethyl-acetic acid, tertiary butylacetic acid, lauryl sulfuric acid,gluconic acid, glutamic acid, hydroxy-naphthoic acids, salicylic acid,stearic acid and muconic acid. Examples of metal salts include saltswith sodium, potassium, calcium, magnesium, aluminum, iron, and zincions. Examples of amine salts include salts with ammonia and organicnitrogenous bases strong enough to form salts with carboxylic acids.

The term “therapeutically-effective amount” refers to an amount of acompound that, when administered to a subject for treating a condition,is sufficient to effect treatment for the condition. “Therapeuticallyeffective amount” can vary depending on the compound, the condition andits severity, the age, and the weight of the subject to be treated.

The term “virus” refers to a submicroscopic infective agent thatincludes a nonliving complex molecule that typically contains a proteincoat surrounding an RNA or DNA core of genetic material but nosemipermeable membrane, that is capable of growth and multiplication inliving cells, and that can cause a disease in humans, animals, orplants.

Compounds of the present disclosure include tautomeric, geometric orstereoisomeric forms of the compounds. Ester, oxime, onium, hydrate,solvate and N-oxide forms of a compound are also embraced by the presentdisclosure. The present disclosure considers all such compounds,including cis- and trans-geometric isomers (Z- and E-geometric isomers),R- and S-enantiomers, diastereomers, d-isomers, I-isomers, atropisomers,epimers, conformers, rotamers, mixtures of isomers and racemates thereofare embraced by the present disclosure.

The descriptions of the various aspects of the present disclosure havebeen presented for purposes of illustration, but are not intended to beexhaustive or limited to the aspects disclosed. Many modifications andvariations will be apparent to those of ordinary skill in the artwithout departing from the scope and spirit of the described aspects.The terminology used herein was chosen to best explain the principles ofthe aspects, the practical application or technical improvement overtechnologies found in the marketplace, or to enable others of ordinaryskill in the art to understand the aspects disclosed herein.

What is claimed is:
 1. A nanorod comprising: a first compound consistingof: a polystyrene block; a poly(N-isopropylacrylamide) block; ammoniummoieties represented by the formula:

 wherein n is an integer of 10 to 100 and each z is independently aninteger of from 1 to 20; ammonium moieties represented by the formula:

 wherein Q is selected from the group consisting of fluoro, chloro,bromo, and iodo, wherein each of m is an integer of 1 to 20 and each qand each x is independently an integer of 1 to 20; a moiety representedby the formula:

 wherein v is an integer of 1 to 20; and a moiety represented by theformula:

 wherein j and p are independently an integer of 1 to 20; or apharmaceutically acceptable salt of the first compound, and a secondcompound consisting of: a second polystyrene block; a secondpoly(N-isopropylacrylamide) block; and a moiety represented by theformula:

 wherein v is an integer of 1 to 20; and a moiety represented by theformula:

 wherein R¹ is selected from the group consisting of —O— and —NH—, andR² is selected from the group consisting of —CH₃ biotin, pyridyldisulfide,

 thiolactonyl, and adamantly, or a pharmaceutically acceptable salt ofthe second compound.
 2. The nanorod of claim 1, wherein R² is pyridyldisulfide.
 3. The nanorod of claim 1, wherein Q is chloro.
 4. Thenanorod of claim 3, wherein the first compound is represented by theformula:

wherein x is an integer of 5 to
 15. 5. The nanorod of claim 1, whereinthe second compound is selected from the group consisting of:

or combination(s) thereof; wherein each s is independently an integer of25 to 35, and each b is independently an integer of 40 to
 50. 6. Thenanorod of claim 1, wherein the first compound is a pharmaceuticallyacceptable salt of a halide.
 7. The nanorod of claim 6, wherein the saltis an iodo salt.
 8. The nanorod of claim 1, wherein a ratio of theinteger n to the integer m is about 5:1 to about 15:1.
 9. The nanorod ofclaim 1, wherein the nanorod has a diameter of about 10 nm to about 20nm.
 10. The nanorod of claim 1, wherein the nanorod has a length ofabout 1 micron to about 2 microns.
 11. A gel comprising the nanorod ofclaim
 1. 12. The gel of claim 11, wherein the gel is an aqueous gel andthe gel comprises about 2 wt % to about 16 wt % nanorod, based on thetotal weight of the gel.
 13. A nanoworm comprising: a first compoundconsisting of: a polystyrene block; a poly(N-isopropylacrylamide) block;ammonium moieties represented by the formula:

 wherein n is an integer of 10 to 100 and each z is independently aninteger of 1 to 20; ammonium moieties represented by the formula:

 wherein Q is selected from the group consisting of fluoro, chloro,bromo, and iodo, wherein each of m is an integer of 1 to 20 and each qand each x is independently an integer of 1 to 20; a moiety representedby the formula:

 wherein v is an integer of 1 to 20; and a moiety represented by theformula:

 wherein j and p are independently an integer of 1 to 20; or apharmaceutically acceptable salt of the first compound; and a secondcompound consisting of: a second polystyrene block; a secondpoly(N-isopropylacrylamide) block; and a moiety represented by theformula:

 wherein v is an integer of from 1 to 20; and a moiety represented bythe formula:

 wherein R¹ is selected from the group consisting of —O— and —NH—, andR² is selected from the group consisting of —CH₃, biotin, pyridyldisulfide,

 thiolactonyl, and adamantly; or a pharmaceutically acceptable salt ofthe second compound.
 14. The nanoworm of claim 13, wherein R² is pyridyldisulfide.
 15. The nanoworm of claim 13, wherein Q is chloro.
 16. Thenanoworm of claim 15, wherein the first compound is represented by theformula:

or a pharmaceutically acceptable salt thereof, wherein x is an integerof 5 to
 15. 17. The nanoworm of claim 13, wherein the second compound isselected from the group consisting of:

or combination(s) thereof; wherein each s is independently an integer of25 to 35, and each b is independently an integer of 40 to
 50. 18. Thenanoworm of claim 13, wherein the first compound is a pharmaceuticallyacceptable salt of a halide.
 19. The nanoworm of claim 18, wherein thesalt is an iodo salt.
 20. The nanoworm of claim 13, wherein a ratio ofthe integer n to the integer m is about 5:1 to about 15:1.
 21. A gelcomprising the nanoworm of claim
 13. 22. The gel of claim 21, whereinthe gel is an aqueous gel and the gel comprises about 1 wt % to about 8wt % nanoworm, based on the total weight of the gel.